WO2009047045A2 - Bioréacteur pour la génération et la stimulation mécanique complexe d'un tissu biologique synthétisé par génie génétique - Google Patents

Bioréacteur pour la génération et la stimulation mécanique complexe d'un tissu biologique synthétisé par génie génétique Download PDF

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Publication number
WO2009047045A2
WO2009047045A2 PCT/EP2008/061338 EP2008061338W WO2009047045A2 WO 2009047045 A2 WO2009047045 A2 WO 2009047045A2 EP 2008061338 W EP2008061338 W EP 2008061338W WO 2009047045 A2 WO2009047045 A2 WO 2009047045A2
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WO
WIPO (PCT)
Prior art keywords
piston
bioreactor
culture chamber
volume
culture
Prior art date
Application number
PCT/EP2008/061338
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English (en)
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WO2009047045A3 (fr
Inventor
Katia Lagana`
Manuela Teresa Raimondi
Gabriele Dubini
Rosaria Santoro
Original Assignee
Politecnico Di Milano
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Publication date
Application filed by Politecnico Di Milano filed Critical Politecnico Di Milano
Publication of WO2009047045A2 publication Critical patent/WO2009047045A2/fr
Publication of WO2009047045A3 publication Critical patent/WO2009047045A3/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M25/00—Means for supporting, enclosing or fixing the microorganisms, e.g. immunocoatings
    • C12M25/14—Scaffolds; Matrices
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M23/00—Constructional details, e.g. recesses, hinges
    • C12M23/34—Internal compartments or partitions
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M35/00—Means for application of stress for stimulating the growth of microorganisms or the generation of fermentation or metabolic products; Means for electroporation or cell fusion
    • C12M35/04—Mechanical means, e.g. sonic waves, stretching forces, pressure or shear stimuli

Definitions

  • Bioreactor for generation and complex mechanical stimulation of engineered biological tissue
  • the present invention relates to a bioreactor as defined in the preamble of claim 1 for generation and mechanical stimulation of engineered biological tissue, such as engineered cartilage.
  • the present invention also relates to a method for mechanical stimulation of engineered biological tissue.
  • Cartilage is a tissue that covers the surface of joints and its functional role relies on its excellent lubricating qualities and on its ability to redistribute, homogenize and damping the loads applied to the joints during motor activity.
  • the properties of this tissue are often affected by traumas to the joint or by the onset of degenerative diseases for which no really effective and final pharmacological or surgical treatment is available to date.
  • the self-regenerative properties of cartilage and its absorption of any administered drugs are limited by its avascularization.
  • the need is highly felt in the field of tissue engineering of growing engineered material so that such material can be stimulated during its growth with the mechanical stresses that the tissue will have to withstand after in-vivo implantation.
  • the provision of correct mechanical stimuli to the growing tissue is part of proper growth of the engineered material to be implanted, whether the latter is a cartilage or a bony or vascular tissue.
  • direct mechanical compression, hydrostatic compression and perfusion of the construct as well as the shear stresses resulting therefrom were found to be important mechanical stimuli in the synthesis of engineered biological tissue, because they reproduce the stresses that the engineered biological tissue will have to undergo after in.vivo implantation.
  • the engineered biological tissue is grown in bioreactors which not only create a controlled environment for the growth of engineered biological tissue but also generate predetermined repeatable stimulation patterns to be imparted to the engineered biological tissue being grown therein.
  • three-dimensional engineered biological tissue requires the presence of scaffolds, i.e. 3D matrices allowing homogeneous cell adhesion and providing a support for cell growth.
  • scaffolds i.e. 3D matrices allowing homogeneous cell adhesion and providing a support for cell growth.
  • the seeded chondrocytes are exposed on scaffolds defined by three-dimensional matrices of polymeric or other type.
  • various types and structures of scaffolds may be provided in response to the features of the desired engineered biological tissue.
  • WO200168800 relates to a bioreactor for generating engineered cartilage with mechanical properties similar to those of the native tissue, particularly a cartilage able to withstand typical physiological loads.
  • This bioreactor allows the growth of chondrocytes seeded on three-dimensional scaffolds by exposing the constructs to mechanical stresses caused by hydrostatic compression and direct compression deformation. These two stresses are obtained by mechanical means, using linear actuators: a platen driven by one of the two actuators compresses the constructs, whereas the other actuator is connected to a piston which pressurizes the cell culture medium.
  • This bioreactor is limited in that it does not all allow the constructs to be submitted to perfusion or any other treatment that can impart shear stresses upon cells, and it does not ensure convective exchange between the cells and the culture medium.
  • CA2543374 relates to a method and a bioreactor for growth and stimulation of three- dimensional vital and mechanically resistant tissues.
  • the bioreactor consists of a culture chamber which is adapted to receive the tissue.
  • a magnetically driven mini-actuator in the culture chamber imparts mechanical stresses to the tissue. Nonetheless, this bioreactor does not provide symmetrical and bidirectional mechanical stresses, cannot ensure and control direct perfusion of constructs and cannot impart hydrostatic compression and shear stresses to the constructs at the same time. In this respect, it shall be noted that simultaneous in-vitro application of such two stresses is useful for the engineered biological tissue to undergo stresses corresponding to those that it will have to withstand in in- vivo situations.
  • This invention is based on the problem of providing a bioreactor for generation and complex mechanical stimulation of engineered biological tissue, that has such structural and functional characteristics as to fulfill the above need, while obviating the above mentioned drawbacks and limitations of prior art bioreactors.
  • This problem is achieved by a bioreactor for generation and complex mechanical stimulation of engineered biological tissue as defined by the features of claim 1.
  • FIG. 1 is a diagrammatic view of a bioreactor of the invention with its actuation means and its control means;
  • FIG. 2 is a diagrammatic sectional view of the bioreactor body with the pistons and the vessels for the culture liquid;
  • FIG. 3 is a simplified cross-sectional view of the bioreactor body with the pistons, the vessels for the culture liquid being omitted;
  • - Figure 4 is a cross sectional view of the bioreactor body only;
  • FIGS. 5a and 5b show a sequence of steps for direct compression treatment of the scaffold by the two pistons
  • FIGS. 8a-8c show a sequence of steps for simultaneous perfusion treatment of the scaffold and liquid change by the two pistons.
  • numeral 1 generally designates a bioreactor for generation and complex mechanical stimulation of engineered biological tissue of the present invention.
  • cell growth of engineered biological tissue conventionally occurs on supports known as scaffolds, i.e. on three-dimensional matrices that can provide homogeneous cell adhesion and growth.
  • scaffolds i.e. on three-dimensional matrices that can provide homogeneous cell adhesion and growth.
  • the seeded chondrocytes are exposed on three- dimensional matrices, e.g. polymeric matrices, which form said scaffolds.
  • the bioreactor 1 comprises:
  • a body 2 defining a culture chamber 3 having a preset volume, which is adapted to be filled with a culture liquid;
  • the support means 4 include scaffold S retention members, defined as scaffold supports 4.
  • the bioreactor body 2 is defined by a hollow cylindrical body, extending in a predetermined axial direction X-X, and preferably but without limitation having a circular cross section.
  • X-X axial direction
  • the opposed ends of the hollow cylindrical body 2 are open.
  • the circular cylindrical shape of the body 2 that may be conveniently made of steel, such as AISI 316L stainless steel, is advantageous in that: - it allows sterilization of the whole volume of the culture chamber 3;
  • the support means 4 i.e. the scaffold support
  • the support means 4 are located at the central cross section of the cylindrical body 2, thereby dividing said preset volume of the chamber 3 into a first volume 3a and a second volume 3b.
  • the scaffold support 4 defines an ideal partition that divides the chamber into said two volumes 3a and 3b. It should be noted that while such division of the chamber into the first volume 3a and the second volume 3b is of geometrical evidence, the presence of the scaffold S has a flow shut-off function but does not prevent the passage and exchange of culture liquid from one volume of the culture chamber to the other.
  • the actuating means include at least one first plunger piston 5 and one second plunger piston 6, each piston 5, 6 being slideably and sealably associated with said body 2 to be received therein and cover a predetermined operating stroke in said chamber 3 from a retracted position (see Fig. 2) to a forward position (see Fig. 5b).
  • Each piston 5, 6 has an end wall and a cylindrical shell.
  • the two pistons 5, 6 face towards each other in mutual opposition and the scaffold S support means 4 are interposed between the two pistons 5, 6.
  • each piston 5, 6 is slideably received into the culture chamber 3 through its respective open end of the latter, to cover a predetermined reversible stroke from a retracted position to a forward end-of-stroke position.
  • the end wall of each piston 5, 6 In the retracted position, the end wall of each piston 5, 6 is located beyond its respective open end of the body 2 to a predetermined limited extent.
  • each piston 5, 6 Conversely, in the forward end-of- stroke position, each piston 5, 6 is received into the body 2 to abutment against the support means 4, so that the front wall of each piston 5, 6 can exert an effective direct compression action on the facing side of the scaffold S retained by the support means 4.
  • the pistons 5, 6 shall cover their respective operating strokes without ever coming out of the hollow cylindrical body 2.
  • first piston 5 operates on the first volume 3a of the chamber 3 and the second piston 6 operates on the second volume 3b of the chamber 3.
  • each piston 5, 6 has circumferential seal housings formed in the cylindrical shell, in which annular seals are held.
  • the bioreactor 1 also has actuating means 8 for actuating the first piston 5 and the second piston 6 as described above.
  • the actuating means 8 allow independent actuation of the first piston 5 and the second piston, thereby allowing either actuation of one piston only or simultaneous and synchronous actuation of both pistons in the same or opposite directions.
  • each piston 5, 6 is connected to a respective motor 10 via transmission means 9.
  • the motor 10 is a stepper motor, which allows accurate control of the piston position within the culture chamber 3 of the body 2.
  • the pistons may be actuated by hydraulic, pneumatic, electromagnetic means or any other type of means that can ensure accurate and fast motion.
  • the bioreactor 1 also includes actuation and control means to manage the operation of the bioreactor and particularly to control the motion of the pistons 5, 6 as better explained hereafter.
  • actuation and control means which also include sensors, data acquisition boards and data processing and storage means 12 are known to those of ordinary skill in the art and will not be further described herein.
  • the bioreactor body 2 has a first transfer port 13 for ensuring fluid communication between the first volume 3a of the chamber 3 and a culture liquid vessel 15, and a second transfer port 14 for ensuring fluid communication between the second volume 3b and a second culture liquid vessel 16. It shall be noted that these vessels are not shown in Figures 1, 3 and 4 for simplicity. o
  • a single vessel may be provided for communication with both transfer ports.
  • the first transfer port 15 is in a position relative to the body 2 corresponding to a substantially central section of the stroke covered by the first piston 5 to move from the retracted position to the forward position.
  • the transfer port 13 is open, i.e. allows fluid communication between the first volume 3 a of the chamber 3 and the vessel 15.
  • the cylindrical shell of the first piston 5 obstructs the transfer port 13, thereby shutting off any fluid communication between the first volume 3a of the chamber 3 and the vessel 15.
  • the first piston 5 operates to shut off fluid flow through the transfer port 13, and can allow or prevent fluid communication between the vessel 15 and the chamber 3 depending on its position in the chamber 3.
  • the second transfer port 14 is also in a position relative to the body 2 corresponding to a substantially central section of the stroke covered by the second piston 6 to move from the retracted position to the forward position.
  • the second piston 6 operates to shut off fluid flow through the transfer port 14, and can allow or prevent fluid communication between the vessel 16 and the culture chamber 3 depending on its position in the chamber 3.
  • the position of the transfer ports 13 and 14 relative to the body 2 may also be other than the above mentioned central position with respect to the stroke of the corresponding pistons 5 and 6 but, according to a preferred embodiment, the transfer ports should not be situated too close to the support means 4.
  • special fluid shut-off valve means may be associated with each transfer port, possibly controlled by said actuation and control means in their opening or closing operation.
  • the transfer ports may be also conveniently placed close to the scaffold support means and, possibly, a single transfer port may be provided instead of two.
  • the body 2 of the bioreactor 1 has a drain port 18 through which the culture liquid contents of the culture chamber 3 may be emptied.
  • the drain port 18 is situated close to the support means 4, with additional fluid shut-off valve means 19 associated therewith and possibly controlled by said and control means in their opening or closing operation.
  • the above described bioreactor 1 allows application of the following mechanical stimuli to the cells seeded on the scaffold S supported by the support means 4:
  • direct compression can be easily applied to cells growing on a scaffold S supported by the support means 4 by moving forward (even independently) both pistons 5, 6 to said forward operating position (see Fig. 5b) in which the front wall of the end of each piston 5, 6 directly abuts against the scaffold S supported by the support means.
  • the direct mechanical compression applied to the in vitro engineered biological tissue may be of constant, cyclic type or changing in any other manner as needed.
  • the pistons 5 and 6 may be simply moved close to each other while the drain port 18 is open (see Fig. 5a). Thus the first volume 3a and the second volume 3b are reduced to zero and the culture liquid contained between the two opposed ends of the pistons 5 and 6 may be conveniently drained from the culture chamber through the drain port 18.
  • pressurization of such liquid may be simply obtained by operating on the two pistons 5, 6 with a suitable force (indicated as F in Figures 6a and 6c) without having the pistons cover an appreciable distance.
  • a pulsating hydrostatic compression stress e.g. having a frequency of 1 Hz and an amplitude oscillating between 15 MPa and 0 MPa, may be applied by simply moving at least one of the two pistons through a negligible stroke away from (see Fig. 6b) and towards the support means 4, from the above described condition in which liquid is pressurized to the desired pressure value.
  • the bioreactor 1 of the invention allows simultaneous application of hydrostatic compression and perfusion (shear) stresses to the cells growing on a scaffold S supported in the chamber 3 by the support means 4.
  • hydrostatic compression and perfusion shear
  • the growing cells of the engineered biological tissue can be submitted to complex stresses (see figures 7a - 7c)
  • the method for complex mechanical stimulation of an engineered biological tissue using a bioreactor of the present invention includes the steps of: - placing a seeded scaffold S on the support means 4 in the culture chamber 3,
  • such small volume is pressurized to a pressure above 10 MPa up to pressure values of 16 MPa, preferably 15 MPa.
  • the bioreactor for generation and complex mechanical stimulation of engineered biological tissue fulfills the above mentioned need and also obviates prior art drawbacks as set out in the introduction of this disclosure.
  • this bioreactor allows the growing cells to undergo the following types of stresses: direct mechanical compression (of constant or cyclic type or varying in any other manner), hydrostatic compression (of constant or cyclic type or varying in any other manner) and shear stress, as well as complex stresses involving simultaneous application of hydrostatic compression and shear stresses.
  • the bioreactor allows effective rinsing of the scaffold S and change of the culture liquid in the culture chamber 3.
  • the bioreactor of the present invention requires no debubbling of the culture chamber, because it avoids the creation of air bubbles, which would affect repeatability of culture tests under both pressure and perfusion.
  • Qualitative studies having the purpose of detecting the evolution of flow lines within the culture chamber, by the use of a marker during the perfusion step, have shown that the fluid dynamics within the culture chamber allows uniform distribution of culture liquid flow all over the surface of the scaffold S, with no detectable flow recirculation or stagnation areas. This ensures uniform stimulation and homogeneous delivery of nutrients to all cultured chondrocytes.
  • the bioreactor of the invention can process with adequate accuracy even very low flows of culture liquid, while allowing application of shear stresses equal to those exerted in in- vivo situations on the seeded chondrocytes. It was found that the stepper motor could be adequately set to define adequate accelerations providing optimal pressurization cycles, such as 0-15 MPa at a frequency of 1 Hz.
  • bioreactor for generation and complex mechanical stimulation of engineered biological tissue of the present invention is that the operation of the bioreactor can be wholly automated and affords generation of a variety of patterns of stimulation of the growing tissue, using an accurate, versatile and easy-to-use control system.
  • An additional advantage of the bioreactor for generation and complex mechanical stimulation of engineered biological tissue of the present invention is the remarkably simple construction of the bioreactor, which ensures simple fabrication and reliable operation.
  • more than two pistons may be provided, e.g. when the culture chamber is defined by a body having multiple branches, such as a T- or cross-shaped chamber.

Abstract

L'invention concerne un bioréacteur pour la génération et la stimulation mécanique complexe d'un tissu biologique synthétisé par génie génétique. Ce bioréacteur comprend un corps (2) définissant une chambre de culture (3) qui est apte à être remplie par un liquide de culture dans lequel un échafaudage est supporté. De façon avantageuse, deux pistons opposés (5, 6) sont reçus de façon coulissante dans ledit corps (2) pour recouvrir une course de fonctionnement prédéterminée dans la chambre de culture (3) d'une position rétractée à une position avant et agissent sur le volume (3) de la chambre de culture (3), ledit échafaudage étant interposé entre les deux extrémités des pistons (5, 6).
PCT/EP2008/061338 2007-10-09 2008-08-28 Bioréacteur pour la génération et la stimulation mécanique complexe d'un tissu biologique synthétisé par génie génétique WO2009047045A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ITMI2007A001945 2007-10-09
ITMI20071945 ITMI20071945A1 (it) 2007-10-09 2007-10-09 Bioreattore per la generazione e la stimolazione meccanica complessa di tessuto biologico ingegnerizzato.

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WO2009047045A2 true WO2009047045A2 (fr) 2009-04-16
WO2009047045A3 WO2009047045A3 (fr) 2010-01-14

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WO (1) WO2009047045A2 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PT106827A (pt) * 2013-03-11 2014-09-11 Univ Aveiro Bioreator de estímulo para caracterização biomecânica de engenharia de tecidos
AU2014215934B2 (en) * 2014-06-25 2016-08-11 University Of Leeds Tissue engineered constructs
EP3498310A1 (fr) * 2017-12-18 2019-06-19 Tornier Procédé in vitro pour créer un tissu conjonctif et/ou un tissu osseux viable
WO2021071885A1 (fr) * 2019-10-08 2021-04-15 Applied Materials, Inc. Agitation par écoulement oscillant à entraînement mécanique
IT201900022350A1 (it) * 2019-12-04 2021-06-04 Hydra S R L Dispositivo di frammentazione di tessuti in ambiente chiuso sterile con procedura asettica e suo metodo

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US6060306A (en) * 1995-06-07 2000-05-09 Advanced Tissue Sciences, Inc. Apparatus and method for sterilizing, seeding, culturing, storing, shipping and testing replacement cartilage tissue constructs
US20010043918A1 (en) * 2000-05-05 2001-11-22 Masini Michael A. In vitro mechanical loading of musculoskeletal tissues
EP1428869A1 (fr) * 2001-08-30 2004-06-16 Takagi Industrial Co., Ltd. Incubateur pour cellules et structures
EP1462515A1 (fr) * 2001-12-05 2004-09-29 Takagi Industrial Co., Ltd. Appareil de culture de tissu/cellules
US20050069426A1 (en) * 2002-03-26 2005-03-31 Christopher Mason Devices for use in medicine
WO2005040332A2 (fr) * 2003-10-21 2005-05-06 Universität Leipzig Procede et bioreacteur pour la mise en culture et la stimulation de greffons cellulaires tridimensionnels, vitaux et mecaniquement resistants

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Publication number Priority date Publication date Assignee Title
US6060306A (en) * 1995-06-07 2000-05-09 Advanced Tissue Sciences, Inc. Apparatus and method for sterilizing, seeding, culturing, storing, shipping and testing replacement cartilage tissue constructs
US20010043918A1 (en) * 2000-05-05 2001-11-22 Masini Michael A. In vitro mechanical loading of musculoskeletal tissues
EP1428869A1 (fr) * 2001-08-30 2004-06-16 Takagi Industrial Co., Ltd. Incubateur pour cellules et structures
EP1462515A1 (fr) * 2001-12-05 2004-09-29 Takagi Industrial Co., Ltd. Appareil de culture de tissu/cellules
US20050069426A1 (en) * 2002-03-26 2005-03-31 Christopher Mason Devices for use in medicine
WO2005040332A2 (fr) * 2003-10-21 2005-05-06 Universität Leipzig Procede et bioreacteur pour la mise en culture et la stimulation de greffons cellulaires tridimensionnels, vitaux et mecaniquement resistants

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PT106827A (pt) * 2013-03-11 2014-09-11 Univ Aveiro Bioreator de estímulo para caracterização biomecânica de engenharia de tecidos
PT106827B (pt) * 2013-03-11 2015-03-11 Univ Aveiro Bioreator de estímulo para caracterização biomecânica de engenharia de tecidos
US10801002B2 (en) 2014-06-25 2020-10-13 University Of Leeds Tissue engineered constructs
US9670443B2 (en) 2014-06-25 2017-06-06 University Of Leeds Tissue engineered constructs
AU2014215934B2 (en) * 2014-06-25 2016-08-11 University Of Leeds Tissue engineered constructs
EP3498310A1 (fr) * 2017-12-18 2019-06-19 Tornier Procédé in vitro pour créer un tissu conjonctif et/ou un tissu osseux viable
WO2019121481A1 (fr) * 2017-12-18 2019-06-27 Tornier Méthode in vitro de création d'un tissu conjonctif et/ou d'un tissu osseux viable
US11577000B2 (en) 2017-12-18 2023-02-14 Tornier In vitro method for creating a viable connective tissue and/or osseous tissue
WO2021071885A1 (fr) * 2019-10-08 2021-04-15 Applied Materials, Inc. Agitation par écoulement oscillant à entraînement mécanique
US11230793B2 (en) 2019-10-08 2022-01-25 Applied Materials, Inc. Mechanically-driven oscillating flow agitation
CN114787426A (zh) * 2019-10-08 2022-07-22 应用材料公司 机械驱动的振荡流搅动
US11585009B2 (en) 2019-10-08 2023-02-21 Applied Materials, Inc. Mechanically-driven oscillating flow agitation
IT201900022350A1 (it) * 2019-12-04 2021-06-04 Hydra S R L Dispositivo di frammentazione di tessuti in ambiente chiuso sterile con procedura asettica e suo metodo
WO2021110282A1 (fr) * 2019-12-04 2021-06-10 HYDRA S.r.l. Dispositif pour la fragmentation de tissus à l'intérieur d'un environnement stérile scellé avec une procédure aseptique et procédé associé

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